Chemical irritation of airway mucosa elicits a variety of reflex responses such as sneezing, apnea, coughing and laryngeal closure aimed to protect the lungs from damage. Nasal mucosa irritation also activates inflammatory and local immune responses aimed to protect the nasal epithelium and avoid disorders affecting the olfactory epithelium. Inhaled irritants can activate either chemo-responsive free nerve endings or solitary chemosensory cells (SCCs) which are specialized chemo-sensitive epithelial cells innervated by the trigeminal nerve. SCCs express elements of the bitter taste transduction cascade, i.e. Tas2R bitter taste receptors, G- protein -gustducin, PLC2 and the TrpM5 transient receptor potential ion-channel (Tizzano et al. 2010). In this proposal, I focus on the downstream action of SCCs as modulators of function of the surrounding epithelial cells including dendritic or macrophage cells of the immune system. I will test the hypothesis that irritant- induced activation of nasal SCCs leads to an immune and/or inflammatory response in the local epithelium. A consequence of that is whether the airway immune cells can be activated and attracted to the chemo-responsive SCCs, and whether SCC excitation activates the immune cells to mature and express new molecular and functional markers. In the proposed studies we will test whether activation of SCCs by an inhaled irritant causes an inflammatory response of the nasal epithelium and determine if SCC activation leads to a local response by macrophages and/or dendritic cells. In order to test whether SCCs are necessary for these responses, we will utilize mice that lack TrpM5 (TrpM5-KO), a transient receptor potential cation channel necessary for SCC function. We previously established that these mice have impaired responsiveness to particular irritants (Tizzano et al. 2010). However, the interactions of SCCs with the surrounding respiratory epithelial or immune cells and the link between SCCs and inflammation after irritant exposure are not understood. To address this issue, the current proposal will determine whether immune cells are recruited by the SCCs in response to an irritant stimulus and whether in response to irritants, the SCCs will lead to a local inflammatory response of the nasal epithelium. These studies will provide the first evidence for an epithelial cell, the SCCs, as a ke receptor cell involved in the local inflammatory and immune responses to irritant compounds. PUBLIC HEALTH RELEVANCE: Chemo-sensitivity of the upper respiratory tract plays an important role in asthma and upper respiratory diseases. Inhaled irritants can activate either chemo-sensitive free nerve endings or trigeminally innervated solitary chemosensory cells (SCCs) to trigger a response. Chemical irritation of the airway mucosa elicits a variety of changes including inflammatory/immune responses as well as respiratory reflexes. The proposed studies will determine whether SCC activation leads to an inflammatory and/or local immune response in the nasal mucosa.